Estimates indicate that addiction cost the U.S. economy neariy one half-trillion dollars per year. The mechanisms driving this behavior are unclear, but involve drug-conditioned cues. In animal models this is attributed to an interaction between dopamine and glutamate neurons In the prefrontal cortex (PFC). However, there remains a lack of understanding ofthe cellular mechanism underiying this interaction. This hampers the development of effective pharmacological treatment strategies for addiction. The long-term objective of this proposal is to identify cellular abnormalities in the PFC that may provide effective therapeutic targets to restore function and thereby prevent relapse to drug seeking. In pyramidal neurons, firing patterns during drug self-administration are regulated in part by dopamine activation of beta-adrenergic receptors (?- AR), which increase intracellular calcium. This activates KCNQ channels to control spike frequency adaptation, which limits the frequency of action potential firing. The central hypothesis of this proposal Is that the ?-AR -signaling cascade is upregulated by chronic cocaine self-administration and depresses KCNQ- mediated inhibition during cue-induced reinstatement of cocaine seeking. To explore the interaction between dopamine and KCNQ-inhibition in PFC neurons, we will record currents mediated by KCNQ that are coupled to of ?-ARs. Patch-clamp recordings will be performed in acute brain slices from rats trained to self- administer cocaine and control (yoked saline) rats, before or after cue-induced reinstatement. The mechanism and functional impact ofthe dopamine-suppressed KCNQ signal on reinstatement is unknown and will be examined in the first two specific aims of this proposal. While activation ofthe prelimbic PFC (PL) initiates cocaine seeking, the projection from the infralimbic PFC (IL) inhibits cocaine seeking. Thus, Aim-2 will examine whether dopamine-suppressed KCNQ signaling is specific to the PL, or also occurs in the IL. Aim-3 will evaluate if manipulation of ?-AR signaling normalizes the KCNQ adaptation during relapse. The results of the proposed experiments are expected to positively influence human health because they should identify novel cellular targets for development of improved therapies to treat drug-seeking behaviors.